1. Field of the Invention
The invention relates generally to methods for preventing post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis in patients. In this treatment, the method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising secretin and a pharmaceutically acceptable carrier.
2. Brief Description of the Related Art
Endoscopic retrograde cholangiopancreatography (ERCP) is a commonly used diagnostic and therapeutic procedure that involves the injection of contrast and the performance of various therapeutic procedures (e.g., stone extraction, stent replacement, and the like). Over 700,000 such procedures are done annually in the U.S. Gastroenterologists perform this procedure for several reasons, including the evaluation of abdominal pain, the diagnosis of gallstones, the evaluation and diagnosis of diseases of the liver and pancreas, and to remove gallstones.
As with any medical procedure, there are risks associated with ERCP. Risks include punctures to the esophagus, bile duct or pancreatic duct, bleeding, and infection. The most common complication that can occur after ERCP is pancreatitis, commonly known as post-ERCP pancreatitis (Baillie J, Endoscopy 26:185-203, 1994; Sherman S, et al., Pancreas 6:350-367, 1991). Post-ERCP pancreatitis can cause a variety of conditions, including substantial morbidity, rare mortality, and increased costs. Its incidence ranges from 1-12% (mean approximately 7%), depending on the patient and the institution (Bilboa M K et al., Gastroenterology 70:314-320, 1976; Cotton P B, Gut 13:1014-25, 1972; Ruppin H et al., Endoscopy 6:94-8, 1974; Nebel O T et al., Gastrointest Endosc 22:34-6, 1975; LaFerla G et al., Pancreas 1:60-63, 1986; Rozler M H J et al., Radiology 157:595-8, 1985; Hamilton I et al., Clin. Radiol. 34:543-6, 1983; Brandes J W et al., Endoscopy 13:27-30, 1981; Nordback I et al., Ann. Chir. Gynaecol. 77:15-20, 1988). The incidence is higher in patients undergoing cholangiography with pancreatography than for those undergoing cholangiography alone, but is significant in both groups (Sherman et al., (1991); LaFerla G, et al., Pancreas 1:60-63 (1986); Skude G et al., Gut 17:127-32 (1976)). The severity of pancreatitis varies from mild, requiring minimal analgesia and outpatient management, to severe leading to the need for hospitalization, surgery, and in rare instances causing death.
A number of factors may play a role in the pathogenesis of post-ERCP pancreatitis. When associated with pancreatography, the pressure of the contrast injection alone can cause pancreatic injury and repeated injections are associated with a higher incidence of pancreatitis. The contrast agents themselves have been suggested to be potentially injurious; however, trials comparing ionic and non-ionic contrast have not shown a consistent difference in the incidence of post-ERCP pancreatitis.
Direct injection of contrast into the pancreatic duct is not the only factor involved in the genesis of post-ERCP pancreatitis, however, as those undergoing cholangiography alone are also subject to this complication. It is likely that irritation, inflammation or induced spasm of the sphincter of Oddi also plays a significant role. Of note, the incidence of post-ERCP pancreatitis increases with number of attempts at duct cannulation.
It is difficult to estimate the costs associated with the management of post-ERCP pancreatitis. Based on the assumption of a 1% risk of severe pancreatitis, a 3% risk of moderate pancreatitis and a 3% risk of mild pancreatitis, the costs can easily exceed 500 dollars per patient. Combined with lost work and productivity, it is clear that an effective prophylactic regimen to prevent post-ERCP pancreatitis would be of great medical benefit.
Many medical interventions have been tried to prevent post-ERCP pancreatitis, including anticholinergics, antihistamines, corticosteroids, and antibiotics. Drugs that have been evaluated in controlled clinical trials include gabexate, somatostatin, octreotide, nifedipine, hydrocortisone, methylprednisolone, prednisone, interleukin-10, non-ionic contrast agents, glucagon, antibiotics, and calcitonin (Jowell P S et al. Gastroenterology 125(2):605, 2003; Renner I G et al., J. Clin. Invest. 72(3):1081-92, 1983; Niederau C et al., Gastroenterology 88(5 Pt 1): 1192-204, 1985; Renner I G et al., Dig. Dis. Sci. 31(3):305-13, 1986; Keim V et al., Hepatogastroenterology 32(2):91-6, 1985; Infantino A et al., Research in Experimental Medicine 190(2):89-93, 1990; Lankisch P G et al., Digestion 26(4):187-91, 1983; Manso M A et al., Peptides 10(2):255-60, 1989; Tymper F et al., Hepatogastroenterology 33(4):159-62, 1986; Kozarek R A et al., Gastrointest. Endosc. 51:AB138, 2000; Information from MD Consult Drug Information on Secretin. Mosby's Drug Consult (© 2003 Mosby, Inc.); Howard-McNatt M et al., Journal of Surgical Research 103; 96-99, 2002). Three agents—somatostatin, its octapeptide analog octreotide, and gabexate mesylate (a protease inhibitor) showed initial promise. Octreotide reduces hyperamylasemia but has not been show to alter the clinical course of post-ERCP pancreatitis. A meta-analysis of 28 clinical trials showed that both prophylaxis with somatostatin and gabexate were effective in reducing the frequency of post-ERCP pancreatitis. However, in two large controlled trials in which pharmacologic prevention was provided to high-risk patients, gabexate, somatostatin and octreotide were each found to be ineffective in preventing post-ERCP pancreatitis. Additionally, a retrospective review of 4833 ERCP procedures suggested secretin might decrease the incidence of post-ERCP pancreatitis in patients without pancreas divisum (Mundorf J B et al., Am. J. Gastroenterology 90(9):1611, 1995; Mundorf J B et al., Am. J. Gastroenterology 90(9):1610, 1995). However, none of these approaches has proved consistently effective in clinical trials.
Examples of treatments for post-ERCP pancreatitis in the patent literature include the following:
U.S. Pat. No. 6,143,306 assigned to Allergan Sales, Inc., discloses a non-radio therapy therapeutic method of treating disorders of the pancreas such as pancreatitis using a neurotoxin such as botulinum toxin.
U.S. Pat. No. 6,261,572 assigned to Allergan Sales, Inc., discloses a method for treating a pancreatic disorder by local administration of a therapeutic amount of a neurotoxin such as botulinum toxin, into or onto the body of the pancreas in order to treat symptoms of a pancreatic disorder.
U.S. Published Patent Application No. U.S. 2003/0132906 assigned to Schering-Plough Corporation, discloses the use of interleukin-10 (IL-10) for the prevention and treatment of pancreatitis. This patent discloses that IL-10 is administered to patients at risk of developing pancreatitis due to a procedure such as ERCP.
U.S. Pat. No. 5,094,837 assigned to Wayne State University discloses a method for using magnetic resonance imaging (MRI) to image the pancreas by using secretin. An amount of secretin is placed in solution and administered to a patient for the purpose of pancreatic imaging. Administration of the secretin is done by IV infusion. The secretin employed in this method can be extracted from porcine or bovine sources or can be genetically recombined porcine, bovine or human secretin.
U.S. Pat. No. 6,020,310 and U.S. Pat. No. 6,498,143, both assigned to Repligen, disclose use of secretin to stimulate pancreatico-biliary fluid secretion in a patient exhibiting autism.
U.S. Pat. No. 6,197,746 assigned to Repligen Corporation discloses methods of using secretin for treating autism.
U.S. Pat. No. 6,365,593 assigned to Repligen Corporation discloses methods of diagnosing individuals for autistic disorders, comprising obtaining a sample of urine from the individuals; measuring a level of a methylxanthine in the urine sample; and comparing the level to a normal control or to a threshold level.
U.S. Pat. No. 6,534,063 to Joan Fallon discloses methods of utilizing the fecal chymotrypsin level of an individual as a measure of the success of secretin, other neuropeptides, and peptides or digestive enzyme administration to such individuals, and in particular, as a prognosticative of potential secretin, other neuropeptides, peptides, and digestive enzyme administration for persons having ADD, ADHD, Autism and other PDD related disorders.
There is a need in the art for a prophylactic treatment or medication for post-ERCP pancreatitis. The present invention is believed to be an answer to that need.